Anti-cancer effects of novel glidobactin type proteasome inhibitors

Proteasome inhibitors are widely used today as an important tool for anti-cancer treatment, which has led to a wide search of novel proteasome inhibitors. Proteasome inhibitors tested in this study are analogues of glidobactin, which are a new class of proteasome inhibitors. Similarly, these compounds effectively inhibit the 26S proteasome activity. In this study, we investigated the cytotoxic effect of these compounds on human multiple myeloma (MM), human Waldenstrom macroglobulinemia (BCWM1), and human lymphocytic leukemia cells (REH). Of the four compounds we tested, T-02 and T-04 were most potent ones and their proteasome inhibitory effect directly correlates with their cell cytotoxicity. Induction of mild ER stress provides a survival benefit to cells, however severe ER stress is known to inhibit proliferation of cells leading to apoptosis. Since a number of proteasome inhibitors have been shown to trigger ER stress induced apoptosis, we investigated whether these novel proteasome inhibitors have this anti-cancer efficacy. Our results suggest that it is indeed the case. We further explored whether the combination of these compounds with other known ER stress inducers leads to aggravated ER stress and enhancement of their anti-cancer efficacy. T-02 or T-04 in combination with thapsigargin (a known inhibitor of sarco/endoplasmic reticulum Ca(2+) ATPase) and dimethyl celecoxib (DMC), an analogue of celecoxib demonstrate enhanced cytotoxic effect with more severe ER stress induction and apoptosis mediated cell death. Taken together, our findings suggest these novel compounds are very effective proteasome inhibitors and trigger the ER stress response with enhanced apoptosis mediated cell death. In addition, in combination with other ER inducer(s), cytotoxic effects of these compounds are highly potentiated.